Multiple recombinant gene transfer vectors based on different viruses have been developed in recent years. Gene transfer vectors based on adeno-associated virus (AAV), i.e., AAV vectors, are preferred due to their ability to transduce different types of dividing and non-dividing cells of different tissues and the ability to establish stable, long-term transgene expression. While vectors based on other viruses, such as adenoviruses and retroviruses may possess certain desirable characteristics, they have also been associated with undesirable side effects. Such side effects have not been detected with gene transfer vectors based on AAV (Manno et al., Nature Medicine, 12(3):342 (2006)).
Many AAV serotypes have been identified, cloned, sequenced, and converted into vectors. These serotypes include AAV8, AAV5, AAV3B and the more recently described AAV-LK03 (WO 2013/029030). However, the present inventors have found that many of the currently used vectors have a low transduction rate in humans. For example, AAV8 vectors have a 20-fold lower transduction in humans than in mice as well as transient, prednisolone responsive, transaminitis which occurred in two-thirds of a high dose cohort. Thus, a need remains for new AAV vectors to improve potency and safety, as well as promoting wider clinical applicability.
To this end, the inventors have developed new hybrid capsids by empirically swapping various domains from 4 different AAV capsids: (1) AAV8, (2) AAV5, (3) AAV3B, and (4) AAV-LK03. Capsids were developed which achieved up to a 5-fold higher level of gene transfer than currently used vectors.